Oligonucleotide-based gene therapy holds tremendous promise for treating a variety of disorders with a genetic basis, including cancers, neurological diseases, and metabolic conditions. However, since its conceptualization in the 1970s, there have only been a relatively small number of commercial successes (e.g., Vitravene, Macugen, and Kynamra), despite powerful advancement in the understanding of the underlying biology. This contrast exemplifies the difficulties in transforming nucleic acids to drugs, which include poor accumulation at target sites, unwanted innate and adaptive immune responses, nuclease degradation, coagulopathy, poor cellular uptake, and overall low biochemical efficacy.
The ability of cationic polymers to complex with nucleic acids and peptides and deliver them to cells has been extensively explored as a route to therapeutic intervention. Despite significant progress, however, these materials are still prone to various degrees of cytotoxic and immunogenic reactions, which limit their clinical application. Recently, a new type of nucleic acid nanostructure, termed spherical nucleic acids (SNAs), emerged as a non-cationic, single-entity transfection agent. Consisting of tens to hundreds of oligonucleotide strands densely arranged onto a spherical core, SNAs are capable of entering cells in large quantities despite their negative charge and knocking down target genes without significant cytotoxicity or stimulation of the innate immune system. Due to the dense arrangement, the SNA oligonucleotides are more stable to nuclease degradation than their free, linear counterparts. However, SNAs interact with protein, such as receptors on the liver, resulting in their capture and uptake by the liver, which limits their residence-time in the blood circulation and hence, ability to reach target cells. Thus, there remain outstanding challenges to the use of oligonucleotides as therapeutics and diagnostic agents and there is a need in the art for methods and delivery systems for delivering oligonucleotides to their target within a cell.